Clinical application of the experimental ADL test for patients with cognitive impairment: pilot study

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Clinical application of the experimental ADL test for patients with cognitive impairment: pilot study
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                OPEN             Clinical application
                                 of the experimental ADL test
                                 for patients with cognitive
                                 impairment: pilot study
                                 Yong‑Hyun Lim1,2, Yookyeong Baek2, Soon Ju Kang3, Kyunghun Kang2 & Ho‑Won Lee2,4*
                                 We employed a hospital-based Internet of Things (IoT) platform to validate the role of real-time
                                 activities of daily living (ADL) measurement as a digital biomarker for cognitive impairment in a
                                 hospital setting. Observational study. 12 patients with dementia, 11 patients with mild cognitive
                                 impairment (MCI), and 15 cognitively normal older adults. The results of 13 experimental ADL tasks
                                 were categorized into success or fail. The total number of successful task and the average success
                                 proportion of each group was calculated. Time to complete the total tasks was also measured.
                                 Patients with dementia, patients with MCI, and cognitively normal older adults performed 13
                                 experimental ADL tasks in a hospital setting. Significant differences in the average success rate of
                                 13 tasks were found among groups. Dementia group showed the lowest success proportion (49.3%)
                                 compared with MCI group (78.3%) and normal group (97.4%). Correlation between classical ADL
                                 scales and the number of completed ADL tasks was statistically significant. In particular, instrumental
                                 ADL (I-ADL) had stronger relationship with the number of completed ADL tasks than Barthel’s ADL
                                 (B-ADL). Dementia group required more time to accomplish the tasks when compared to MCI and
                                 normal groups. This study demonstrated that there is a clear relationship between the performance
                                 of experimental ADL tasks and the severity of cognitive impairment. The evaluation of ADLs involving
                                 the IoTs platform in an ecological setting allows accurate assessment and quantification of the
                                 patient’s functional level.

                                   Activities of daily living (ADL) are utilized routinely as predictors of health and function among community-
                                   dwelling older adults to detect the early onset of disability to enable appropriate care management. Currently,
                                   the approaches for assessment are inadequate, lacking reliability, sensitivity, and validity. It is, therefore, critical
                                   to have instruments that would be more sensitive in detecting preclinical stages of functional decline.
                                       Accomplishing routine ADLs requires several fundamental abilities: cognitive, motor, and perceptual
                                 ­abilities1. Among these abilities, impairment in cognitive function hinders overall performance of ADLs of
                                   older adults, which could interrupt with their independent ­living2. Therefore, evaluating the decline in ADLs is
                                   crucial for cognitively impaired patients to enable assessment of their actual functional status and decide whether
                                   a patient would need assistance with daily tasks. Besides, the accurate assessment of ADLs contributes to the
                                   diagnosis of cognitive disorders, including dementia and mild cognitive impairment (MCI). Longitudinally,
                                   changes in ADL performance could be monitored through the course of the cognitive disorders to investigate
                                   the progression or improvement with medications.
                                       Classical ADL assessment relies on patient-reported outcomes in which the patients provide responses
                                   regarding their statuses themselves or indirect ratings from informants such as caregivers. However, consid-
                                   ering patients’ old age and cognitive dysfunction, the accuracy and reliability of self-rated questionnaires are
                                  ­doubtable3. Furthermore, previous research has proven a disagreement between indirect ADL ratings from
                                                                                    ­ atients4,5. Caregivers tend to overestimate their ADL assistance
                                   caregivers and the actual functional statuses of p
                                   and report lower levels of the functional status of patients, compared with patients’ direct assessment; thus,

                                 1
                                  Center of Self‑Organizing Software‑Platform, Kyungpook National University, Daegu, South Korea. 2Department
                                 of Neurology, School of Medicine, Kyungpook National University, 80 Daehakro, Bukgu, Daegu 41566,
                                 Korea. 3School of Electronics Engineering, College of IT Engineering, Kyungpook National University, Daegu, South
                                 Korea. 4Brain Science and Engineering Institute, Kyungpook National University, Daegu, South Korea. *email:
                                 neuromd@knu.ac.kr

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Clinical application of the experimental ADL test for patients with cognitive impairment: pilot study
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                                            indicating that the indirect measurement using questionnaires has unequivocal limitations in that the subjective
                                            evaluation of ADLs is susceptible to bias and errors.
                                                Several studies have attempted direct measurement of ADLs in a home or experimental s­ ettings6–9. The use of
                                            sensor-based technology for the recognition and classification of ADLs at home environment has been proposed
                                            in many ­studies9–11. Some of them used body-mounted systems that allow data quantitation, along with disease
                                            risk and early detection, while others utilized non-intrusive ambient sensor systems that enable capturing of
                                            environmental data for cumulative measurements. These evaluations have proven that those with body-mounted
                                            sensors, as well as non-intrusive ambient sensors could distinguish and classify different ADLs successfully by
                                            detecting and quantifying patients’ behaviors. Furthermore, it has been shown that differences in ADL pattern-
                                            performance between dementia patients and healthy controls are detectible with the use of unobtrusive in-home
                                           ­sensors12. On the other hand, there have been attempts to measure ADLs by direct observation and performance
                                            quantification of ADL tasks in a laboratory ­environment6. Assigning identical tasks to every participant in a
                                            controlled setting provides more objective and reliable data regarding the performance of ADLs.
                                                In light of a need for direct measurement of ADLs, it is highly desirable to assess ADLs with real-time
                                            observations. On top of that, it is essential to control different variables which can exist in the living space by
                                            implementing an experimental space where ADLs can be evaluated. And unlike previous studies that focused
                                            on observing and categorizing various ADL performances, we made it possible to compare cognitive functions
                                            in a more objective way by having all participants perform the same type of ADLs.
                                                We employed a hospital-based Internet of Things (IoT) platform to validate the role of digital real-time ADL
                                            measurement for cognitive impairment, as the next steps in the progress of the development of the IoT devices.
                                            In the course of the advancement of this IoT instrument, there have been many studies on various platforms
                                            for the recognition of daily activities in the living environment and/or monitoring the deterioration of cogni-
                                            tive ­abilities13–17. While video- or microphone-based platforms are remarkable in detecting human activities
                                            technically, concerns over maintaining privacy have been raised. Installing videos and microphones in the most
                                            private space and transmitting the information on daily lives to an external server are likely to fail approval by
                                            the general population, despite their technological advantages.
                                                Our IoT instruments platform was constructed with deliberation on the optimal balance between privacy
                                            and technical feasibility. A series of processes, including distinguishing a person’s identity, deciding whether a
                                            person’s behavior is in the normal range or not without videos or microphones, and transmitting the information
                                            to caregivers or a designated community care center requires highly sophisticated technologies.
                                                We hypothesize that there would be considerable differences in the performance of the experimental tasks
                                            depending on the degree of cognitive impairment of the study participants. At the same time, we explored the
                                            potential of the hospital-based IoT platform in assessing ADLs for clinical decision-making. With the results
                                            from this platform, we analyze the discriminant power of the experimental tasks to determine if the real-time
                                            measurement of ADLs would have clinical significance in distinguishing the cognitively impaired patients.

                                           Results
                                           Analysis of the task success proportion and task completion time. Figure 1 shows the success
                                           proportion of the thirteen tasks. The average success proportions of the normal control group, MCI group, and
                                           the dementia group were 97.4%, 78.3%, and 49.4%, respectively (95% confidence interval ­[CIcontrols] = 87.56%–
                                           107.31, ­CIMCI = 66.79%–89.85%, ­CIdementia = 38.32%–60.40%; P < 0.001). Among the three groups, the dementia
                                           patients showed the lowest average success proportion. Overall, among the 13 different tasks that were subjected
                                           to completion, the type of task that involved using a microwave oven (task 12) demonstrated the lowest success
                                           proportion while entering the test room (task 1) demonstrated the highest success. In the analysis of task com-
                                           pletion time, there were significant differences among the three groups regarding the time it took to complete
                                           the tasks (95% ­CIcontrols = 34.89–50.47, ­CIMCI = 47.02–64.71, ­CIdementia = 62.65–80.43; P < 0.001). On average, the
                                           dementia group required more time to complete the tasks, compared with the MCI group (95% CI = 3.03–28.32;
                                           P < 0.05) and normal control group (95% CI = 16.61–41.10; P < 0.001). Among the tasks, moving to the kitchen
                                           (task 9) required the longest amount of time, while entering the test room took the least amount of time (task 1).
                                           In summary, dementia patients needed more time to finish the tasks and yet showed the least successful perfor-
                                           mance, whereas the normal group performed most of the tasks successfully with the least time.
                                               Figure 1A shows both the total task completion time and the total number of successful tasks for all partici-
                                           pants. As shown in Fig. 1 B-C, the task success proportions and task completion time of the dementia group
                                           turned out to vary in distribution among the patients. On the other hand, the normal group demonstrated a
                                           more homogeneous distribution pattern with the success proportions and the time it took to complete the tasks.
                                           The MCI group exhibited an in-between distribution pattern, being more variable than that of the normal group
                                           but more homogeneous than that of the dementia group. These distribution patterns of the three assessment
                                           groups indicate that there were systematic differences in task performances among them, which correlated with
                                           each group’s cognitive function.

                                           Linear discriminant analysis (LDA) for the digitalized ADL task. Table 1 shows LDA conducted
                                           based on the performance of each participant group. Three models were constructed with the independent
                                           variables, which consisted of criteria for distinguishing each cognitive group, and the group variables, which
                                           were three cognitively different groups. Model 1 consisted of the scores from clinical scales, including Korean
                                           version of Mini-Mental State Examination (K-MMSE), Korean version of Expanded Clinical Dementia Rating
                                           scale (CDR), Global Deterioration Scale (GDS), Barthel Index Activity of Daily Living (B-ADL), and the Korean
                                           version of Instrumental Activity of Daily Living (I-ADL), and Model 2 only included scores from B-ADL and
                                           I-ADL. Lastly, Model 3 employed the results of 13 experimental tasks. The classifiers were compared with each

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Clinical application of the experimental ADL test for patients with cognitive impairment: pilot study
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                                 Figure 1.  Alluvial diagram and group difference for the task activities. (A) Alluvial diagram showing the total
                                 completion time and total success frequency of each group and all participants as a flow of data. (B) Group
                                 difference in task success rate. (C) Group difference in task completion time.

                                                                Eigenvalues (canonical
                                            Wilks’ lambda       correlations)                SVDa
                                  Model     LD1       LD2       LD1            LD2           LD1     LD2   Discriminant hit ratio (%)
                                  Model 1   0.04***   0.51***   11.24 (0.96)   0.97 (0.70)   13.6    4.2   100%
                                  Model 2   0.34***   0.99      1.94 (0.81)    0.01 (0.11)    5.8    0.5   67.6%
                                  Model 3   0.09***   0.66      5.96 (0.93)    0.52 (0.58)   10.02   3.1   89.5%

                                 Table 1.  Model comparison of linear discriminant analysis. LD1 linear discriminant function 1, LD2 Linear
                                 discriminant function 2, Model 1 MMSE + CDR + GDS + B-ADL + I-ADL, Model 2 B-ADL + I-ADL, Model
                                 3 task 1 + task 2 + … + task 13. Class variable(or target variable) of all models was group, SVD singular value
                                 decomposition-compute ‘lda function’ of R MASS package. *** p < 0.001.

                                 other with regards to how effectively a model could classify the participants according to their cognitive level.
                                 Linear discriminant function 1 (LD 1) and 2 (LD 2) were extracted from each model. The values from LD 1 of
                                 Wilks’ lambda were lower than those from LD 2 of Wilks’ lambda. In contrast, the values from LD 1 of Eigen-
                                 values were higher than those from LD 2 of Eigenvalues. Moreover, the values of LD 1 in all the three models
                                 were statistically significant (Model 1; χ2 = 101.84, P < 0.001, Model 2; χ2 = 36.58, P < 0.001, Model 3; χ2 = 68.39,
                                 P < 0.001). Model 1 showed the highest discriminant power (canonical r = 0.96, SVD = 13.6), as this model com-
                                 prised the individual variables which had been used to discriminate against the experimental groups in the
                                 first place. Model 2, which was constructed with B-ADL and I-ADL, excluded the cognition assessment scales
                                 (MMSE, CDR, GDS) in order to compare with Model 3, which showed the lowest discriminant power among
                                 the classifying groups (canonical r = 0.81, SVD = 5.8). The misclassification rate of Model 2 was highest among

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                                           Figure 2.  The results of LDA and correlation analysis. (A) Biplot of LDA with 5 clinical scales as
                                           predictors(MMSE, CDR, GDS, B-ADL, I-ADL). (B) Biplot of LDA with 2 ADL clinical scales as predictors(B-
                                           ADL, I-ADL). (C) Biplot of LDA with 13 experimental ADL tasks used in this study(“t1” = task1. predictor
                                           variables; task1 + task2 + …. + task13). (D) The Spearman’s correlation between the total task success frequency
                                           and the clinical ADL scales.

                                           the three models (31.5%). Although Model 3 revealed lower discrimination hit ratio, compared with Model 1, it
                                           showed a higher discriminant hit ratio (89.5%) than Model 2 (67.6%).
                                              Figure 2A–C represents how the LDA classifier was utilized to classify the cognitively different participants
                                           into three groups using standardized coefficients of linear discriminants. The larger the coefficient, the more
                                           significant the contribution of each independent variable in the group’s discrimination.

                                           The relationship between the clinical ADL scores and the number of successful tasks. An asso-
                                           ciation between the scores obtained on the clinical ADL scales (B-ADL and I-ADL) and the results of 13 experi-
                                           mental tasks was identified. Figure 2D reveals that I-ADL scores of participants significantly correlated with the
                                           performance of nine tasks (t4; hand washing, t5; hand wiping, t7; measuring blood pressure, t8; using pillbox, t9;
                                           ambulating, t10; using a gas stove, t11; using a coffee machine, t12; using a microwave oven, t13; ambulating).
                                           In particular, the results of using microwave oven (task 12) and the gas stove (task 10) showed the strongest cor-
                                           relation with I-ADL scores (rho =  − 0.75; rho =  − 0.64, P < 0.05, respectively), followed by the result of ambulating
                                           (task 9; rho =  − 0.57, P < 0.05). On the other hand, B-ADL scores were significantly related to only four of the
                                           tasks (t4; hand washing, t5; hand wiping, t9; ambulating, t12; using microwave oven).

                                           Discussion
                                           The goal of this study was to evaluate the ADL of normal older adults and cognitively impaired patients using
                                           IoT devices and network technologies and to verify their effectiveness in the hospital setting. ADL performance
                                           of three cognitive groups of dementia patients, MCI patients, and normal participants was evaluated using 13
                                           experimental tasks. We used an IoT-based platform to measure participants’ task success proportion and task

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                                  completion time and statistically confirmed how effectively these results could classify the groups. Accordingly,
                                  the ADL experimental tasks among patients with dementia had the lowest success proportion and the longest
                                  completion time of task time. When it came to the distribution pattern of the results, the greater the severity
                                  of the group’s cognitive decline, the more heterogeneous the distribution pattern of the individual patient was.
                                  Additionally, the classifier composed of the ADL experiment tasks showed greater discriminant power to dis-
                                  tinguish three cognitive groups than the classifier composed of B-ADL and I-ADL scores.
                                      Through this experiment, it was evident that there are systemic statistically significant differences in the per-
                                  formance of ADL tasks relative to the different cognitive levels of the three groups. The dementia group showed
                                  the worst performance among the three groups, while the MCI patients showed better performance than the
                                  dementia patients but not as good as the normal participants. Thus, the results of performing the experimental
                                  tasks, which are derived from ADLs in real life, are likely to reflect the deterioration of patients with cognitive
                                  impairment in their living environment.
                                      Our analysis(LDA) that looked at how well the experiments in this study could distinguish the groups which
                                  had already been separated by clinical scales. It was proved that the classifier created using the results of the
                                  experimental task distinguished the clinical groups to a precise degree, although the task of evaluating the cogni-
                                  tive function itself was not included in the experiment. These results are consistent with the purpose of this study,
                                  set to quickly and accurately measure the ability to perform ADLs in a clinical scene by recognizing the success
                                  or failure of the task using IoT devices. Moreover, the results of this study not only show the technical feasibil-
                                  ity and clinical usefulness of the IoT technology but also suggest the potential of the IoT devices to advance in
                                  their development into a useful platform that could evaluate ADLs accurately, while satisfying the conditions to
                                  protect the privacy of patients. The advantage of such privacy protection can lead to the use of the IoT devices
                                  as a method to measure ADLs in the daily life of patient.
                                      Among the different types of ADL, it has been demonstrated that the decline in I-ADL is more sensitive to
                                  MCI or early dementia than B-ADL because I-ADL deteriorates when higher cognitive function is ­impaired18–21.
                                  The experimental tasks in this study included both types of ADL tasks; those involving ambulating and main-
                                  taining hygiene represent B-ADL, and those involving utilization of different instruments (sphygmomanometer,
                                  Smart Pill Reminder, coffee machine, gas stove, and microwave) represent I-ADL. The fact that the performance
                                  results of the tasks have a stronger correlation with I-ADL than the B-ADL suggests that the tasks in this study
                                  could better detect the deterioration of early cognitive function in a like manner as I-ADL.
                                      The major limitation of this study trace to the experimental procedures because participants with hearing
                                  impairment or gait disturbance were excluded who might have difficulties in performing the tasks successfully
                                  despite normal cognitive function. Meanwhile, since the tasks of evaluating ADLs are limited to a few, it could
                                  not fully represent activities in daily life consisting of hundreds of older adults. In the same vein, evaluations
                                  of social activities, outings, and financial management have not yet been incorporated into the tasks due to
                                  constraints in the laboratory setting. Also, unlike previous studies in which ADL was assessed over a period of
                                 ­time12,22, this was a point-in-time assessment and possibly not fully demonstrate the participants’ daily living
                                  skills in their homes or a facility.
                                      Regarding the IoT platform, despite its several advantages, which include the short duration of measure-
                                  ment time, high-level of patients’ privacy, and autonomous network system among the devices, the platform
                                  exhibited a relatively high frequency of errors during the experiment (12.15%), and thus, needs to be improved
                                  in future studies.
                                      In conclusion, the evaluation of ADLs using the IoT platform demonstrated a clear correlation between
                                  cognitive function and ADL performance. The results of ADL performance showed a substantial determinant
                                  power in regard to classify the participants into three cognitive groups. The significant association between I-ADL
                                  score and ADL performance also suggests that the direct ADL measurement can prove its value in detecting early
                                  stage of cognitive decline. Furthermore, the measurement of ADLs in a hospital setting showed the potential to
                                  provide clinicians with evidence to understand the cognitive level of patients and tools to follow up on changes
                                  in cognitive function in the course of the patient’ disease.

                                 Method
                                 Participants. We conducted an observational study with an enrollment of a total of 38 participants, 12
                                 dementia patients, 11 MCI patients, and 15 normal controls, recruited via the clinic in the Department of Neu-
                                 rology at Kyungpook National University Chilgok Hospital, Daegu, South Korea. We excluded patients with fol-
                                 lowing conditions. (1) Patients with major psychiatric illnesses according to the criteria of DSM-IV, (2) patients
                                 who has been treated with chronic kidney disease, chronic respiratory disease, malignant tumor, and uncon-
                                 trolled diabetes or hypertension. (3) Patients with systemic conditions that are known to cause dementia (e.g.,
                                 hypothyroidism, vitamin B or folic acid deficiency, niacin deficiency, hypercalcemia, neurosyphilis, HIV infec-
                                 tion), (4) Patients with substance-induced conditions, (5) patients with profound hearing loss, blindness, or gait
                                 disorder which makes it difficult to be ­tested23.

                                 Ethical considerations. This study was approved by the Institutional Review Board of Kyungpook
                                 National University (approval No. 2018-0149). All procedures about this study were explained to the partici-
                                 pants and a written informed consent was obtained prior to participation. Patients with dementia and mild
                                 cognitive impairment provided their own written informed consent. Also informed consent was obtained from
                                 legally authorized representatives of the dementia and with mild cognitive impairment participants. The study
                                 was conducted following the principles established in the Helsinki Declaration update of 2008.

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                                                                                                                                Overall F test
                                            Parameters                        NC               MCI                 Dementia     P value          Post-hoc
                                            Age                               69.1 ± 6.6       71.3 ± 9.0          76.2 ± 7.2   P < .001         a
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                                 task. The RD and MID used two different communication methods, low frequency (LF) and Bluetooth low energy
                                 (BLE). When a participant performed an experimental task, the LF signal was generated from the RD to wake
                                 up the nearby MID, and the BLE enabled the RD to gather the information regarding the participant’s identity
                                 and the distance from the MID. Furthermore, this combination of LF and BLE allowed the RD in every entrance
                                 to detect a participant’s access to the MID. In this study, we used this method to capture data on the movement
                                 of the participants tagged with the MID.
                                     The location anchor hub (LAH) was placed in every unit space (10 × 10 cm) to collect data from the RD and
                                 MID in the same area and perform self-analysis of the data, whereby, it distinguishes the results of the tasks
                                 and decide whether it would repeat the recorded prompt or allow the participant to proceed to the next task.
                                 The LAH also gathered the received signal strength indicator of BLE, advertising from the MID so that it could
                                 broadcast a task-specific prompting, according to the presumed location of the MID. The LAH experiments
                                 automatically measure the ADL and analyze the results, including the task performance and task completion
                                 time based on the recorded data.

                                 ADL measurement. Thirteen experimental tasks were developed for the measurement of the ADL (see Fig. 3).
                                 The performance of each task was recorded by a sensor-based platform at a general neurology ward in a univer-
                                 sity hospital. A recorded verbal prompting was broadcasted from the LAH before each task to assist the initiation
                                 of a task and to give a specific instruction regarding performing each task. All participants performed the same
                                 sequence of the tasks according to the verbal prompting. When they completed a task, regardless of the result
                                 was a success or failure, the prompting for the next task was broadcasted automatically.
                                     A number was assigned to each task according to the sequence of the task performance. The procedure
                                 started from entering the test room (Task 1), followed by entering the toilet in the test room (Task 2). Then the
                                 participants were instructed to use the toilet (Task 3) and navigate to the sink (Task 4). After washing hands at the
                                 sink (Task 5) and wiping hands by a paper towel (Task 6), participants measured their own blood pressures with
                                 a sphygmomanometer (Task 7) in the test room. Subsequently, they were asked to use the Smart Pill Reminder,
                                 which provided pills automatically (Task 8). Next, participants were directed to the kitchen outside the test room
                                 (Task 9) and operate the gas stove (Task 10), followed by using the coffee machine (Task 11) and the microwave
                                 (Task 12) in the kitchen. Finally, they were asked to go back to the test room, where they initiated the experiment
                                 (Task 13). All the tasks except Task 5 were measured by the SRD. The ESD detected participants’ hands washing
                                 at the sink (Task 5). When a participant equipped with a MID initiated a sequence of the tasks, the measuring
                                 devices autonomously communicated with each other, and restored data, based on the participants’ location,
                                 the results of task performance, and task completion time in a memory device.

                                 Statistical analysis. Data preprocessing, data visualization, correlation analysis, and Linear Discriminant
                                 Analysis (LDA) was conducted by R software (version 3.6.3., 2020-02-29). We verified the relationship between
                                 the clinical ADL parameters (B-ADL, I-ADL) and thirteen ADL tasks using Spearman’s correlation coefficient
                                 (rho). Statistical Package for Social Sciences (SPSS Version 25, IBM) was used for LDA, a repeated-measured
                                 analysis of variance (ANOVA), and descriptive statistics. One-way ANOVA was used for participants’ demo-
                                 graphics. The success proportion and task completion time were analyzed using repeated-measures ANOVA.
                                 Wilks’ lambda, Eigenvalues, and Discriminant hit ratio of three LDA models were calculated with SPSS. P-values
                                 for a two-tailed test were selected and P < 0.05, P < 0.01, and P < 0.001 were considered significant when compar-
                                 ing demographics, LDA, correlation, and ANOVA.

                                 Received: 31 August 2020; Accepted: 23 November 2020

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                                           Acknowledgements
                                           We thank the patients and their families, as well as neuropsychologists Ji-Eun Joung and Hye-Won Jeong, for
                                           their generous help with patient recruitment. This work was supported by the Basic Science Research Pro-
                                           gram through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-
                                           2018R1A6A1A03025109) of the Republic of Korea.

                                           Author contributions
                                           H.W.L. and S.J.K. conceptualized, designed, and supervised this study. Y.H.L. performed the experiments, pro-
                                           cessed the experimental data, performed the analysis, interpreted the results, and drafted the manuscript. Y.B.
                                           aided in interpreting the results and worked on the manuscript. Y.H.L. and Y.B. contributed equally to this study.
                                           All authors discussed the results and commented on the manuscript.

                                           Competing interests
                                           The authors declare no competing interests.

                                           Additional information
                                           Correspondence and requests for materials should be addressed to H.-W.L.
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                                           © The Author(s) 2021

          Scientific Reports |   (2021) 11:356 |                     https://doi.org/10.1038/s41598-020-78289-z                                                                         8

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